BACKGROUND Members of the HMGN protein family modulate chromatin structure and influence epigenetic modifications. HMGN1 and HMGN2 are highly expressed during early development and in the neural stem/progenitor cells of the developing and adult brain. Here, we investigate whether HMGN proteins contribute to the chromatin plasticity and epigenetic regulation that is essential for maintaining pluripotency in stem cells. RESULTS We show that loss of Hmgn1 or Hmgn2 in pluripotent embryonal carcinoma cells leads to increased levels of spontaneous neuronal differentiation. This is accompanied by the loss of pluripotency markers Nanog and Ssea1, and increased expression of the pro-neural transcription factors Neurog1 and Ascl1. Neural stem cells derived from these Hmgn-knockout lines also show increased spontaneous neuronal differentiation and Neurog1 expression. The loss of HMGN2 leads to a global reduction in H3K9 acetylation, and disrupts the profile of H3K4me3, H3K9ac, H3K27ac and H3K122ac at the Nanog and Oct4 loci. At endodermal/mesodermal genes, Hmgn2-knockout cells show a switch from a bivalent to a repressive chromatin configuration. However, at neuronal lineage genes whose expression is increased, no epigenetic changes are observed and their bivalent states are retained following the loss of HMGN2. CONCLUSIONS We conclude that HMGN1 and HMGN2 maintain the identity of pluripotent embryonal carcinoma cells by optimising the pluripotency transcription factor network and protecting the cells from precocious differentiation. Our evidence suggests that HMGN2 regulates active and bivalent genes by promoting an epigenetic landscape of active histone modifications at promoters and enhancers.

中文翻译：

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在多能干细胞模型中，干细胞的鉴定需要通过HMGN2维持活跃的染色质状态。

背景技术HMGN蛋白家族的成员调节染色质结构并影响表观遗传修饰。HMGN1和HMGN2在早期发育过程中以及在发育中和成年大脑的神经干/祖细胞中高度表达。在这里，我们调查HMGN蛋白是否有助于染色质可塑性和表观遗传调控，这对于维持干细胞的多能性至关重要。结果我们显示，多能胚胎癌细胞中Hmgn1或Hmgn2的丢失导致自发性神经元分化水平增加。这伴随着多能性标记物Nanog和Ssea1的缺失，以及前神经转录因子Neurog1和Ascl1的表达增加。从这些Hmgn基因敲除系衍生的神经干细胞还显示出自发性神经元分化和Neurog1表达增加。HMGN2的丢失导致H3K9乙酰化的整体减少，并破坏了Nanog和Oct4位点的H3K4me3，H3K9ac，H3K27ac和H3K122ac的分布。在内胚层/中胚层基因中，Hmgn2敲除细胞显示出从二价构型向抑制型染色质构型的转换。但是，在其表达增加的神经元谱系基因上，未观察到表观遗传变化，并且其二价状态在HMGN2丢失后得以保留。结论我们得出结论，HMGN1和HMGN2通过优化多能性转录因子网络并保护细胞免于过早分化来保持多能性胚胎癌细胞的身份。